Trans-sclera portal for delivery of therapeutic agents

ABSTRACT

A portal through the sclera for delivery of an effective amount of therapeutic agent to the back of the eye.

FIELD OF THE INVENTION

The instant disclosure relates to the delivery of pharmaceuticals andthe like to the back of the eye and, more particularly, to a portalthrough the sclera for delivery of an effective amount of therapeuticagent to the back of the eye.

BACKGROUND

There are three primary structures within the human eye that areessential to vision and subject to age-related damage: the cornea, lensand retina. The retina is a multi-layered sensory tissue that lines theback of the eye. It contains millions of photoreceptors that capturelight rays and convert them into electrical impulses. These impulsestravel along the optic nerve to the brain where they are turned intoimages. There are two types of photoreceptors in the retina: rods andcones. The retina contains approximately 6 million cones. The cones arecontained in the macula, the portion of the retina responsible forcentral vision. They are most densely packed within the fovea, the verycenter portion of the macula. Cones function best in bright light andallow us to appreciate color. There are approximately 125 million rods.They are spread throughout the peripheral retina and function best indim lighting. The rods are responsible for peripheral and night vision.The retina is essential for vision and is easily damaged by prolongedunprotected exposure to visible and near visible light. Light-inducedretinal pathologies include cystoid macular oedema, solar retinopathy,ocular melanomas and age-related macular degeneration (ARMD).Light-induced retinal damage is classified as structural, thermal orphotochemical and is largely determined by the exposure time, powerlevel and wavelength of light.

In healthy adults the retina is generally protected from the most severeforms of light-induced damage by the outer eye structures, including thecornea and crystalline lens. The cornea is a transparent proteinaceousocular tissue located in front of the iris and is the only transparenteye structure exposed directly to the external environment. The corneais essential for protecting the delicate internal structures from damageand facilitates the transmission of light through the aqueous humor tothe crystalline lens.

The crystalline lens is an accommodating biological lens lying in backof the cornea, anterior chamber filled with aqueous humor, and the iris.Between the lens and the retina is the vitreous chamber filled withvitreous humor. The optical pathway through the eye acts to refract thelight entering the eye, with the cornea providing most of the opticalpower, and the accommodating lens facilitating the convergence of bothfar and near images onto the retina. Ocular elements in the opticalpathway absorb various wavelengths of light, while permitting others topass through. In the normal human eye, only wavelengths of light betweenabout 400 nm and 1,400 nm can pass through the refracting elements ofthe eye to the retina. However, high transmittance levels of blue andviolet light (wavelengths from about 390 nm to about 500 nm) has beenlinked to conditions such as retinal damage, macular degeneration,retinitis pigmentosa, and night blindness.

Intraocular pressure (IOP) in the eye can significantly affect theelements of the ocular pathway, and is maintained by the formation anddrainage of aqueous humor, a clear, colorless fluid that fills theanterior and posterior chambers of the eye. Aqueous humor normally flowsfrom the anterior chamber of the eye out through an aqueous outflowchannel at a rate of 2 to 3 microliters per minute.

Glaucoma, for example, is a progressive disease of the eye characterizedby a gradual loss of nerve axons at the optic nerve head. In many cases,the damage to the optic nerve head is due to increased intraocularpressure. This increase in pressure is most commonly caused by stenosisor blockage of the aqueous outflow channel, resulting in excessivebuildup of aqueous fluid within the eye. Other causes include increasein venous pressure outside the eye which is reflected back through theaqueous drainage channels and increased production of aqueous humor. Ina “normal” eye, IOP ranges from 8 to 21 mm mercury. In an eye withglaucoma, IOP can range between normal pressures up to as much as 50 mmmercury. This increase in IOP produces gradual and permanent loss ofvision in the afflicted eye.

Existing corrective methods for the treatment of glaucoma include drugs,surgery, and implants. In many cases therapy can require delivery ofvarious therapeutic agents to various portions of the eye over a lengthyperiod of time, typically by injection of the agent directly into theeye.

There are numerous examples of surgical procedures that have beendeveloped in an effort to treat victims of glaucoma. An iridectomy,removal of a portion of the iris, is often used in angle-closureglaucoma wherein there is an occlusion of the trabecular meshwork byiris contact. Removal of a piece of the iris then gives the aqueoushumor free passage from the posterior to the anterior chambers in theeye. A trabeculotomy, opening the inner wall of Schlemm's canal, isoften performed in cases of developmental or juvenile glaucoma so as toincrease the outflow of the aqueous humor, thereby decreasing IOP. Inadults, a trabeculectomy shunts fluid through a trapdoor flap in the eyethat performs a valve-like function for the first few weeks aftersurgery.

While often successful, these surgical techniques possess inherent risksassociated with invasive surgery on an already afflicted or compromisedeye. Furthermore, the tissue of the eye can scar over this small areaand the eye reverts to the pre-operative condition, therebynecessitating the need for further treatment.

Ocular implants are sometimes used in long-term glaucoma treatment. Oneearly implant is called the Molteno Implant, after A. C. B. Molteno. Theimplant is a small circular plate with a rigid translimbal drainage tubeattached. The plate was 8.5 mm in diameter and formed a surface area ofabout 100 mm². This implant is sutured to the sclera in the anteriorsegment of the eye near the limbus and the drainage tube is insertedinto the anterior chamber of the eye. Once implanted, the body formsscar tissue around the plate. Fluid causes the tissue above the plate tolift and form a bleb into which aqueous humor flows from the anteriorchamber via the drainage tube. A bleb is a fluid filled space surroundedby scar tissue, somewhat akin to a blister. The fluid within the blebthen flows through the scar tissue, at a rate which can regulate IOP.

A newer implant has been redesigned for insertion into the posteriorsegment of the eye to avoid problems with early designs. This implant isreferred to as a long tube Molteno implant. The implant comprises aflexible drainage tube connected to one or more rigid plate reservoirs.The plates are shaped to conform to the curvature of the eye. Thereservoir plate is placed under Tenon's capsule in the posterior segmentof the eye and sutured to the sclera. The drainage tube is implantedinto the anterior chamber through a scleral incision. However, the longtube Molteno implant is still disadvantageous, as the plates are formedof a rigid plastic which makes insertion beneath the eye tissuedifficult and time-consuming.

After such an implant is attached, IOP tends to fall as aqueous fluidflows immediately through the drainage tube. However, an open drainagetube may release too much of the fluid too fast, which is detrimental tothe eye. It is not until 2-6 weeks later that the bleb forms around theplate to sufficiently regulate the fluid flow. Some prior devices havetherefore incorporated valves in the fluid drain path designed tofunction for a limited time until the bleb forms. However, such valveddevices sometimes clog later, requiring another surgery.

More recently introduced implants feature a flexible plate that attachesto the sclera, and a drainage tube positioned for insertion into theanterior chamber of the eye. A bleb forms around the plate and fluiddrains into and out of the bleb to regulate IOP. This type of shunt iscalled a Baerveldt shunt. One such device has an open tube with no flowrestricting elements. Temporary sutures are used to restrict fluid flowfor a predetermined period after which the bleb forms and fluid drainageis properly regulated. The temporary sutures are either biodegradable orremoved in a separate procedure. This method works well, but the timingof suture dissolution is inexact and may operate improperly, and asecond procedure undesirable.

Some shunts also include fenestrations through the plate to promotefibrous adhesion, which may reduce bleb height. Though a bleb is thoughtto have a beneficial function in regulating aqueous humor diffusion, toolarge of a bleb may cause the patient some pain or may be aestheticallyunacceptable. Some doctors even prefer to use anti-proliferatives suchas mitomycin C or 5-FU at the time of surgery to prevent formation ofthe fibrous bleb. Another potential complication is endophthalmitis, aninflammation of the internal tissue of the eye. This complication mayoccur in any intraocular surgery, with possible loss of vision and evenof the eye itself. Infectious etiology is the most common cause, andvarious bacteria and fungi have been isolated as the cause of theendophthalmitis. The risk of infection is more pronounced early in ashunt implant procedure, when a passage to the interior of the eye iscreated and fluid flows therethrough. Later, the bleb acts as a filterto prevent microorganisms such as bacteria from entering the eye.

Some eye diseases can be treated with pharmaceuticals. However, wherethe diseases primarily affect the back of the eye, it can be difficultto administer and achieve effective levels of therapeutic agents in thatportion of the eye. Such diseases are typically treated by directinjection of biologically active pharmaceutical agents, such asanti-inflammatory steroids and target-specific antibodies. Treatment mayentail repeated injections that can put the patient at risk ofcomplications involving conditions such as infection, endophthalmitis,high intraocular pressure (IOP), glaucoma, cataract, retinal detachmentand bleeding, and lack of wound-healing. A new approach is needed thatcan deliver pharmaceuticals and the like to the back of the eye whilemitigating the adverse effects that attend the prior art. However, anysolutions requiring patient compliance or repeated injection run therisk of failure due to noncompliance of the patient.

SUMMARY OF THE DISCLOSURE

An apparatus and method for delivery of an effective amount oftherapeutic agent to the back of the eye via a portal through the sclerais disclosed. In an embodiment of the present invention, the portalcomprises an implantable shunt for repeated injection of ophthalmicpharmaceutical treatments into an eye. The shunt and associated methodmay include a partition wall or septum configured to provide separationbetween the intraocular and intraorbital spaces of the eye. The wall maybe re-sealable or self-healing after each injection.

The implantable shunt and associated method may also comprise a swellloadable polymeric ocular insert with a micron scale tab that, wheninserted into the eye, may extend through the sclera into theintravitreal space as a transport channel. Such a tab may wick atherapeutic agent from the insert into the intravitreal space. It is tobe understood that both the foregoing general description and thefollowing detailed description are exemplary and explanatory and areintended to provide further explanation of the invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings are included to provide a furtherunderstanding of the invention, and are incorporated in and constitute apart of this specification. The drawings illustrate disclosedembodiments and/or aspects and, together with the description, serve toexplain the principles of the invention, the scope of which isdetermined by the claims.

In the drawings:

FIG. 1A illustrates a human eye in cross section.

FIG. 1B illustrates in greater detail the portion of the eye of FIG. 1Aenclosed in the dotted box.

FIG. 2A is an exemplary embodiment of a shunt in accordance with thedisclosure.

FIG. 2B illustrates in greater detail the front portion of FIG. 2A.

FIGS. 2C and 2D illustrate various exemplary embodiments of shunts inaccordance with the disclosure.

FIGS. 3A, 3B, and 3C illustrate other disclosed exemplary embodiments.

FIG. 4A illustrates an agent-loadable contact lens used in conjunctionwith a trans-sclera portal.

FIG. 4B is a micrograph of a portion of the contact lens of FIG. 4A.

DETAILED DESCRIPTION

The figures and descriptions provided herein may be simplified toillustrate aspects of the described embodiments that are relevant for aclear understanding of the herein disclosed processes, machines,manufactures, and/or compositions of matter, while eliminating for thepurpose of clarity other aspects that may be found in typical opticaland surgical devices, systems, and methods. Those of ordinary skill mayrecognize that other elements and/or steps may be desirable or necessaryto implement the devices, systems, and methods described herein. Becausesuch elements and steps are well known in the art, and because they donot facilitate a better understanding of the disclosed embodiments, adiscussion of such elements and steps may not be provided herein.However, the present disclosure is deemed to inherently include all suchelements, variations, and modifications to the described aspects thatwould be known to those of ordinary skill in the pertinent art.

FIG. 1A illustrates a human eye in cross section with the eye in anupward orientation relative to the page. FIG. 1B illustrates in greaterdetail the portion of the eye of FIG. 1A enclosed in the dotted box. Therelevant structures of the eye are described briefly to providebackground and context for anatomical terms incorporated herein. Anumber of anatomical details have been omitted for clarity.

Referring to FIG. 1A, the sclera is a tough outer membrane of the eyethat covers most of the eye except the portion in the front of the eye,which is covered by the cornea. The sclera forms the posteriorfive-sixths or so of the connective tissue coat of the eyeball. Itmaintains the shape of the eyeball, and is resistant to internal andexternal forces. It also provides attachments for the extraocular muscleinsertions. The choroid is a vascular layer lying adjacent to the insidesurface of the sclera. It contains connective tissue to the sclera onthe outside, and to the retina on the inside. The choroid providesoxygen and nourishment to the outer layers of the retina. The retina isa light-sensitive layer of tissue, adjacent to the choroid and liningthe inner surface of the globe of the eye. The optics of the eye createan image of the field of vision on the retina, which initiates processesthat ultimately trigger nerve impulses. The impulses are conveyed by theoptic nerve to the visual centers of the brain.

The cornea is the transparent anterior (front) part of the eye thatcovers the iris, pupil, and anterior chamber. Light enters the eyethrough the cornea, proceeds through the aqueous humor in the anteriorchamber, through the pupil, lens, and vitreous humor, and on to theretina. The cornea, lens, and humors refract the light to form the imageon the retina, with the cornea accounting for approximately two-thirdsof the eye's total optical power. The pupil is defined by an aperture inthe iris, which is located in front of the lens.

The cornea merges into the sclera at a juncture called the limbus. Theciliary muscle and ciliary processes form the ciliary body, located nearthe limbus on the inside surface of the eye. Aqueous humor is secretedby the ciliary processes, and passes through the pupil into the anteriorchamber, which is defined by the space between the iris and the cornea.In a healthy eye, the aqueous humor is absorbed through the trabecularmeshwork, then proceeds through Schlemm's canal and on through veinswhich merge into venous blood circulation. Intraocular pressure (IOP) ismaintained in the eye largely by the balance of secretion, absorption,and outflow of the aqueous humor through the mechanism described above.

The vitreous humor (or humour) is a clear gel that fills the spacebetween the lens and the retina of the eye, called the vitreous chamber.Unlike the aqueous humor which is dynamic and continuously replenished,the vitreous humor is static and is not replenished. One common abnormaleye condition, glaucoma, is a disease in which the optic nerve at theback of the eye is damaged in a characteristic manner. Abnormally highfluid pressure in the aqueous humor in the anterior chamber is asignificant risk factor for developing glaucoma. If left untreated,glaucoma can lead to permanent damage of the optic nerve and resultantvisual field loss, which can progress to blindness.

Another condition, Macular Degeneration (MD), which may be Age-related(AMD), results in a loss of vision in the center of the visual field dueto damage to the central region of the retina, called the macula.Specifically, the macula is an oval-shaped spot near the center of theretina at the back of the eye, with a diameter of about 1.5 mm. Towardthe center of the macula is the fovea, a small pit that contains thelargest concentration of cone cells in the eye and is thus responsiblefor central, high resolution vision. Consequently, degeneration of themacula can result in the loss of abilities that require sharp centralvision, such as reading.

Treatment for these and other conditions often includes the introductionof therapeutically effective agents, including but not limited to drugs,into the vitreous chamber of the eye. In the prior art, the most commonway to introduce such agents is by injecting them directly into the eye,and in many cases the course of treatment requires repeated injections.This can put the patient at risk of complications such as infection,endophthalmitis, high intraocular pressure, glaucoma, cataract, retinaldetachment and bleeding, and poor wound-healing. Recently, the use ofocular shunts is becoming more and more common. Most commonly, the shuntmay be implanted under a flap cut into the sclera, with a flow tubeinserted into the anterior chamber of the eye. This may allow theaqueous humor to drain, preventing intraocular pressure (IOP) fromrising too high. The humor typically drains into a plate that isimplanted underneath the flap in the sclera to form a blister-likechamber called a bleb. A common and potentially catastrophic earlypostoperative complication is hypotony, i.e., excessive leakage ofaqueous humor resulting in low intraocular pressure. Extreme hypotonycan cause a devastating deflation of the eyeball. Thus, common methodsof treatment are fraught with challenges. The herein disclosedapparatus, systems, and methods can be used to address some of thosechallenges.

Referring now to FIG. 2A, a shunt 200 may be implanted through thesclera of the eye and on into the vitreal chamber. When implanted, theshunt has a proximal end 210 protruding through the surface of thesclera, and a distal end 220 within the vitreal chamber. Preferably, theshunt may be inserted into the eye in a manner to position the distalend near to the back of the eye that is being treated. The shunt mayprovide access to the interior of the eye for a plurality ofapplications of pharmaceutical agents to the back of the eye whilemitigating potential complications from repeated intraocular injections.In an embodiment of the present invention, at least a portion of theouter and/or inner surface(s) of the shunt, particularly where it passesthrough the sclera, may be coated with one or more agents, such assilver ions, anti-proliferative drug/polymer coatings, and/orantibiotics, to mitigate the possibility of trans-scleral infectionand/or inflammation.

In alternative arrangements, the distal end of a shunt tube may beintroduced into the anterior chamber instead of into the vitrealchamber. If so, miotic agents such as pilocarpine may also be deliveredwith the shunt to increase the outflow of aqueous humor to alleviatehigh IOP.

As shown in FIG. 2B, in an embodiment of the present invention the shuntmay comprise a hydrogel portion 230 that contains one or morepharmaceutical agents to be introduced into the eye. The hydrogelportion may be formed into an appliance that is placed at the surface ofthe sclera in the intraorbital space, or alternatively, under a flapthat is surgically cut into the sclera. The appliance may be formed withone or more edges or tabs that contain holes by which it can be suturedinto place. Preferably, the hydrogel may be formed of a non-degradablebiomedical material having well accepted biocompatibility. As such,there are a plurality of acceptable hydrogel and non-hydrogel materialsfor use in the instant invention.

By way of non-limiting example, hydrogels having varying degrees ofequilibrium water uptake (such as in a range of 5% to 500% w/w) may besynthesized by reacting combinations of monomers and macromers asdiscussed immediately below and by way of non-limiting example only.Monomers leading to high water content hydrogels may include acrylicmonomers, hydroxyethylmethacrylate (HEMA), vinylalcohol, Methacryloylphosphorylcholine (MPC), Acrylamide (Am), di-methyl aminoethylmethacrylate (DMAEMA), and acrylic acid (AA). Macromers leading to highwater content hydrogels may include sodium polyacrylate, polyurethane,PEG, hydrophilic segmented polyurethane urea, polyether block amide,hydrophilic polyamide, agarose, carboxymethyl cellulose, alginate,chitosan, hyaluronan, and Glycosaminoglycan (GAG) such as heparansulfate.

Correspondingly, and also by way of non-limiting example only, monomersleading to minimal to low water content polymeric structures may includemethyl methacrylate monomer (MMA) and perfluorinated mononers. Macromersleading to minimal to low water content polymeric structures may includepolyurethane, polyurethane urea, polypropylene copolymers, polyetherblock amide, polyamide, thiol-ene polymers, and Diels-Alder polymers.

In another embodiment illustrated in FIG. 2C, the shunt may provide asafe portal for a plurality of injections, and may not extend far pasteither the interior or exterior surface of the eye wall. As shown, theshunt may include a self-healing septum 240 that may act as a partitionwall to provide physical separation between the intraocular andintraorbital spaces, while maintaining a safe conduit for repeatedneedle insertion. The septum may be disposed at any convenient locationat or near the sclera. In certain embodiments, the outer and/or innersurface(s) of the shunt may be coated with one or more agents, such assilver ions and/or antibiotics, to mitigate the possibility oftrans-scleral infection. The septum is preferably constructed of asilicone elastomer, although other materials may be used. In addition,the shunt may be formed of or include polymers or polymer compositeswith added healing agents, catalysts, or reactive agents that mayprovide enhanced mechanical performance and resistance to degradationand oxidation. Healing of polymer materials can also be induced byapplying heat, ultraviolet light (UV), or an electric field to theshunt. For example, heating may encourage further polymerization torepair a damaged shunt and/or UV light may initiate free radicalpolymerization to repair a damaged shunt. Alternatively or in addition,silicone elastomers may be incorporated with polymerization initiatorsthat yield silanolate end groups capable of living type reactions viaheating.

Unwanted increase in intraocular pressure (IOP) may arise due torepeated intraocular injections. This can be treated or prevented withone or more of prostaglandin analogs, beta blockers, alpha agonists, andcarbonic anhydrase inhibitors. Anti-inflammatory and immunosuppressantagents such as dexamethasone or other corticosteroids or corticosteroidderivatives, and mammalian Target Of Rapamycin (mTOR) inhibitors mayserve to treat multiple eye diseases such as uveitis. Further,antibiotics such as besifloxacin, ciprofloxacin, moxifloxacin,azithromycin, and the like may also be included in treatments to preventmicrobiologic growth due to repeated intraocular injections.

In an alternative embodiment illustrated in FIG. 2D, the shunt 250 maybe resealed with a biocompatible polymer plug 260 after each injection.The plug may be impregnated with one or more timed-release therapeuticagents before being inserted within the shunt tube. Timed-releasetherapeutic agents may include, for example, prostaglandin analogs (e.g.Xalatan, Lumigan, Travatan Z), Beta blockers (e.g. timolol), alphaagonists (e.g. Alphagan P, iopidine), carbonic anhydrase inhibitors, orcombinations of these. Corticosteroids, dexamethasone, mTOR inhibitors,paclitaxel, Eylea (a Vascular Endothelial Growth Factor (VEGF)receptor), anti-VEGF antibodies, Avastin, and Lucentis can also beapplied. In embodiments, the plug may be used in conjunction with aseptum of self healing polymer biomaterial located in the interior ofthe shunt. The plug may include a structure 270 that fits into ahomologous structure in the shunt 250, which together serve to securethe plug within the shunt and prevent its inadvertent removal.

In certain embodiments, at least a portion of the shunt may be formed byextrusion from a thermoplastic polymer in a relative biocompatiblesolvent such as N-methylpyrrolidone or a solvent/water based mixture.One method of installing a shunt is to use a small gauge needle tocreate a track through the sclera into which the shunt is inserted.Alternatively, a laser may be used to create the track.

Further, in certain embodiments, the shunt may include an element builtinto the shunt's internal lumen to prevent over-reaching of the needlethat injects the therapeutic agent, which could potentially damageocular components such as the lens or the retina. One such element is aninternal lumen of gradually decreasing diameter, ending in a diameterthat is a smaller gauge than that of a select ophthalmic injectionneedle, or of a range of commonly used needles. Alternatively, a shuntlumen may be designed to be used in conjunction with a homologous orotherwise compatibly designed injection needle, which together implementa stopper element to prevent accidental damage to internal eyestructures.

Additionally, in an embodiment, a coating of antibiotic drug may beapplied to the shunt by spray coating, direct fluid application, and/ordip coating. The coating may also be ablated on the outer surface of theshunt, or on both outer and internal surfaces. The coating may includeextracellular matrix materials such as biocompatible polymers orhydrogels, to provide improved adhesion and stability of the shunt atthe trans-scleral implant site. Such materials may be naturally derived,or may be synthetic. For example, naturally derived materials mayinclude alginate, collagen, and the like. Synthetic materials mayinclude poly(vinylidene fluoride-co-hexafluoropropene) (PVDF-HFP), otherfluorinated polymers, crosslinked polyethylene glycol,polylactide-co-glycolide, and the like.

In embodiments, sustained therapeutic agent delivery may be achievedthrough use of a plug impregnated with one or more time release agents.For relatively rapid release (e.g., in the range of a short portion ofone day to several days) a water soluble excipient, such aspolyvinylpyrrolidone (PVP) or a cellulosic, may be used to form theplug. For sustained release over a period of time lasting from a fewdays to several months, such as for a small molecule drug, the plug maybe formed from or using hydrophobic polymers. This type of plug caninclude materials such as poly-DL-lactide (PDLLA),polyvinylidenefluoride-co-hexafluoropropylene (PVDF-HFP),polylactic-co-glycolic acid (PLGA), PCL,poly(ethylene-glycol-b-(DL-lactic acid-co-glycolic acid)-b-ethyleneglycol (PEG-PLGA PEG), and PLGA-PEGs may be utilized as the matrixpolymer. For larger molecular weight biologics, a hydrogel type matrixsuch as crosslinked PVP, polyethylene glycol (PEG), or biopolymers maybe utilized. In embodiments, the hydrogel may be delivered as a liquid,to then gel in situ within the shunt. The shunt may also be formed toprovide a sustained outflow of drug solution over time.

In embodiments, the shunt can be designed to be osmotic and swell whenhydrated, and to release the pharmaceutical agent in a sustained mannerover time. A pressure sensitive design may also be used to allow forfluid outflow, for example, in the case when intraocular pressure ishigh, to thereby alleviate high IOP.

The shunt may also incorporate a plurality of flow-through conduits,each conduit serving its own distinct purpose. For example, a dualconduit configuration may be used, wherein one conduit is adapted toreceive repeated injections using fine gauge needles, while the otherconduit allows for fluid outflow as necessary during injection, and/orto alleviate subsequent high IOP complications. Other numbers andcombinations of conduits may be incorporated into a shunt to provide anydesired combination of shunt capabilities, which may be based on, by wayof non-limiting example, drug particle size, required or desired volume,or the like.

Referring now to FIG. 3A, another form of re-loadable, trans-scleralinsert is illustrated for sustained release of anti-angiogenic drug inthe posterior segment of the eye. Here, a swell loadable hydrogel insert300 may have a micron scale tab 310 (shown much exaggerated forvisibility) which juts out of the sclera as an external mass transportchannel when the shunt is implanted. A therapeutic agent may beimpregnated into the hydrogel. The agent may be or include therapeuticcells, such as stem cells. Agent-loaded nanoparticles (Np) can also, oralternatively, be impregnated into the gel.

As shown in FIG. 3B, the shunt may be used as, or in conjunction with, adrug depot 320 for sustained drug release. The depot 320 may be disposedin the vitreous chamber as shown, or can be disposed on the surface ofthe sclera or surgically placed under a scleral flap. Therapeutic agentsthat can be loaded into the depot and released over time can includepaclitaxel, anti-VEGF antibodies, and other anti-VEGF biologics for thetreatment of retinal eye diseases such as wet age-related maculardegeneration, diabetic retinopathy, and macular edema, among others.Therapeutic agents may also be delivered to treat conditions that mightotherwise arise after tube-shunt surgery, such as to reduce scar tissueand/or to prevent infection.

In an exemplary operation, at the end of a round of therapeutic agentdelivery near the exhaustion of the agent reservoir, a fresh agentsolution may be added to the reservoir, for example, by the applicationof eyedrops or an eyewash. The agent may wick through the hydrogel tab,through the trans-sclearal pathway, and on into the intravitreal space,where it may be conveyed to the vitreous humor.

In an exemplary embodiment, the hydrogel insert may be or comprise ananotube or other strand with an external diameter in the range of about100 nm to about 2 μm. Alternatively, the implant may be or comprise athin film having a thickness in the range of about 500 nm to about 2 μm.In either case, the proximal end of the strand or film (hereinaftercollectively “strand”) creates a wicking window through the sclera, andthe distal end can deliver the therapeutic agent to the vitreous humor.

Alternatively, as shown in FIG. 3C, a swell loadable hydrogel strand 330may be inserted between the choroid and the sclera, again with a micronscale tab 310 jutting out of the sclera at the proximal end as anexternal mass transport channel. In such an embodiment, the distal endof the strand 340 may be placed near to the area being treated. Thereby,the choroid and sclera may hold the insert in place to provide adelivery pathway directly to the area being treated. The hydrogel insertmay open into the vitreous space through a trans choroidal access, asshown. Alternatively, the insert may not open into the vitreous space.Instead, the agent can diffuse into the choroidal blood vasculature totreat the back of the eye.

In short, the insert is preferably outside the visual field uponimplantation, and should remain so. Accordingly, the insert may beimplanted anywhere about the posterior segment of the eye, and may besized and shaped so as not to provide the possibility of impairment ofthe visual field. Moreover, in the event of failure of the insert orentry into or affect on the visual field by the insert, the insert maybe removed.

A hydrogel for use with the present invention may be made of or includePEG, PVP, GAG, PAA, CMC, CPMC, HPMA hyaluronic acid, Poloxamer F127,functionalized PEG, PVA, HEMA, silicon gels, sodium alginate, PolyMPC,etc., and/or a combination of these. At the end of a round oftherapeutic agent delivery and near the exhaustion of the agent supplystored in the insert or in a reservoir coupled thereto, a fresh agentsolution may be simply added to the strand, for example, using eyedrops,an eyewash, or other method of recharging the storage medium. The agentmay wick through the hydrogel tab and through the trans-sclera tunnelinto the swell loadable insert, and/or to the distal end of the strand.

In certain embodiments, a hydrogel or polymeric insert may bereversible, and/or may be triggered to release its therapeutic agent ondemand via appropriate stimuli. For example, the stimuli may beelectroactive (e.g. polyaniline); pH sensitive (e.g., administration ofslightly acidic eye drops), or temperature sensitive (e.g.,administration of cold drops to eye). The stimuli may also be based onlight sensitivity (e.g., administration of ultraviolet light, orwell-aimed laser light directed at the insert), or enzyme sensitivity(e.g., administration of an enzyme to increase insert degradation andaccelerate drug release). Further, an immunosuppressant and/oranti-proliferative agent such as Zotarolimus may be used to coat theshunt to mitigate certain conditions that may arise from the use of theshunt. One or more other agents may also be used in conjunction withZotarolimus. For example, Zotarolimus plusan anti-tumor necrosis factor(anti-TNF) can be used.

In yet other embodiments, drug conjugation into macromers for sustainedrelease via lability-controlled dissociation of the active agent fromthe macromeric prodrug may be utilized. Here, the drug may beconjugated, for example, into Hyaluronic acid, GAG through ester bond oranhydride bonds, or other chemically labile bonds. In such anembodiment, a macromeric prodrug may be injected intravitreally. Thelabile bong may release the drug over time. Alternatively, the drug maybe conjugated into Vitrosin (collagen in IVT) and injectedintravitreally. The drug can be conjugated into these polymers as apendant group, or in endgroups, for example, PEG, PVP, GAG, PAA, CMC,CPMC, HPMA hyaluronic acid, PolyMPC, etc/, or a combination of these.The drug can also be conjugated into dynamers and injectedIntravitreally. In this way, drug release may depend on H-bondingstrength.

In certain embodiments, the drug may be conjugated into Hyaluronic acid,

GAG through ester bond or anhydride bonds or other chemically labilebonds. The macromeric prodrug may be injected intravitreally, and thelabile bong may release the drug over time. Alternatively the drug maybe conjugated into Vitrosin (collagen in IVT) and injectedintravitreally. The drug may be conjugated into these polymer as apendant group or endgroups, such as PEG, PVP, GAG, PAA, CMC, CPMC, HPMAhyaluronic acid, PolyMPC etc and/or a combination of these.

In embodiments, conjugated bonds may release a drug in response toexposure to fluorescent light. Thereby, drug delivery may be controlledon demand. The macromeric prodrug may again be delivered intravitreally,and the labile bong may release the drug on demand using a Fluorescenttrigger. Alternatively the drug may be conjugated into Vitrosin(collagen in IVT), and/or into dynamers, and delivered intravitreally.Drug release may still depend on H-bonding strength and use of afluorescent trigger.

In embodiments, conjugated bonds may be or include physical bonds suchas H-bonding, electrostatic interaction, Hydrophobic interaction, Au—Sbonds, or the like. This may enable sustained release drug deliverywithout covalent chemical bond formation. The physical complexation ofan active agent with an excipient may not change any chemical bonds inthe drug structure, and hence may not be considered a new entity. Thedrug can be complexed with Hyaluronic acid and/or other GAG and theninjected Intravitreally. Either small molecular weight (MW) drugs orbiologics, or both, can be included in this configuration. In additionto complexation with polymers already mentioned, oligomeric andmonomeric entities may also be used for physical complexation with thedrug, such as Glycerol, Mannitol, Mannose-6-phosphate, and the like.

In an embodiment of the present invention a drug coated angioplastyballoon (not shown) may be used to treat retinal diseases such as AMD,macular edema, and diabetic retinopathy. A drug may be conjugated intoHyaaluronic acid through an ester bond or anhydride bonds. Themacromeric prodrug may be delivered intravitreally as describedhereinbefore, and the labile bong may release the drug over time.Alternatively, a drug may be conjugated into Vitrosin (collagen in IVT)and delivered intravitreally. In embodiments, a drug may be conjugatedinto such polymers as a pendant group or as end-groups, for example,PEG, PVP, GAG, PAA, CMC, CPMC, HPMA hyaluronic acid, PolyMPC, or thelike, and/or a combination of these. A drug may also be conjugated intodynamers and delivered intravitreally, and drug release may depend onH-bonding strength as before. Anti-angiogenic and neuroprotective drugscan include, for example, ABT-869 (multi-targeted kinase inhibitor),Aurora Kinase inhibitor (ABT-348 and 993), JAK Kinase (ABT-317), TSP-1(ABT-898, 567), 81 P1 (ABT-413), Zotarolimus, Bcl-2 (ABT-199), Bcl-2 BU,Cal pain, RGMa antibody, DLL-4 Ab, PGDF antibodies, pKC small moleculeinhibitors, DVD-Ig molecules combining VEGF, DLL-4, PGDF, EGFR Ab, andRGMa binding domains, and/or combinations of these.

In certain embodiments, a drug may be conjugated into hyaaluronic acid,but through bonds that may release drug in response to a fluorescentlight trigger to enable drug delivery on demand. A macromeric prodrug,for example, may be delivered intravitreally, and the labile bong mayrelease the drug on demand by use of the fluorescent trigger.Alternatively, a drug may be conjugated into Vitrosin (collagen in IVT)and delivered intravitreally and/or conjugated into the followingpolymers as a pendant group or as end-groups: PEG, PVP, GAG, PAA, CMC,CPMC, HPMA hyaluronic acid, PolyMPC, etc., and/or a combination ofthese. The drug may also be conjugated into dynamers and deliveredintravitreally. Once again, drug release may depend on the H-bondingstrength and fluorescent trigger.

In embodiments, sustained release of an anti-angiogenic drug may beperformed in the posterior segment of the eye using an implanted devicethat may not be particulate. A micron-size absorbable polymericmonolithic implant (such as a ribbon, mat, stent, disc, cylinder, etc.)may be loaded with an anti-angiogenic drug. The implant surface may becoated as described previously. The implant may be deployed either byintravitreal delivery in a buffer, or in a viscous, lubricious vehiclesuch as haluronic acid. Such a drug may be impregnated into a monolithicstructure (such as an absorbable stent) or coated on the surface (thestructure may incorporate pores to hold the drug). Thereby, the quantityof drug and the rate of drug release may be tailored by adapting thesize and quantity of pores to suit the particular application.Illustratively, the structure may be embodied as a stent, which may beplaced in the back of the eye away from the field of vision, and apposedat the bottom of the retinal wall. Similarly, the surface of the stentcan be coated with swellable hydrophilic polymer such as PEG, PVP, MPC,etc. so that little to no trauma is induced to the retina.

In certain alternative embodiments, an absorbable Np loadedanti-angiogenic drug may be embedded in a slowly dissolvable strip. Oneor more such strips may be injected into intravitreal space. An Npembedded strips may be placed in multiple locations in IVT. Such adissolvable strip may be made of or comprise PEG, PVP, GAG, PAA, CMC,CPMC, HPMA hyaluronic acid, PolyMPC, etc., and/or a combination ofthese. The strip may be blended with hydrophobic excipient such asstearate, palmitate, or poly glycerol sebacate. Thereby, tailored andcontrolled dissolution of therapeutic agents loaded into the strip maybe enabled. In embodiments, an agent may also be loaded in the strip fora bolus initial release. For example, Np may be impregnated into thestrip as sub populations based on size and shape. This may also modulatedrug release rate. In such embodiments, the strip may be blended with ahydrophobic excipient such as stearate, palmitate, or poly glycerolsebacate. This may enable tailoring controlled dissolution of the strip,as before. Zotarolimus may also be used as an active agent. As may beappreciated by those skilled in the art, multiple drugs may also beused. For example, Zotarolimus may be used in conjunction with anti-TNF.

Turning now to FIG. 4A, an illustration of an embodiment of adrug-loadable contact lens is shown. The lens 400 may function as anordinary contact lens, except that it is made of or includes a portionmade of so-called block-copolymers. In a block-copolymer, the copolymeris microphase separated to form a periodic nanostructure that may beused as a depot to store the therapeutic agent. The nanostructure mayprovide storage regions that are small enough to not scatter light, andhave miscibility with the agent, thereby providing for a controlledrelease of the agent.

FIG. 4B illustrates an exemplary block copolymer nanostructurecomprising a matrix 410 in which microphase separated regions 420 may beembedded. The matrix, which makes up most of the lens, may be orcomprise a conventional hydrogel such as HEMA or a silicone material.The regions where the drug is stored may be of a more hydrophobicnature, such as PEA, polymers made through metathesis polymerizations,and controlled free radical polymerization, to provide very well definedblock sizes. Used in conjunction with a shunt comprising one or morestrands having a micron scale tab protruding from the surface of thesclera, the contact lens may serve as a repository of therapeutic agentthat is absorbed over time by the strand(s), and wicks through thesclera into the vitreal chamber, or between the sclera and choroid tothe treatment site.

Although the invention has been described and illustrated in exemplaryforms with a certain degree of particularity, it is noted that thedescription and illustrations have been made by way of example only.Numerous changes in the details of construction, combination, andarrangement of parts and steps may be made. Accordingly, such changesare intended to be included within the scope of the disclosure, theprotected scope of which is defined by the claims.

1-29. (canceled)
 30. A method of treating a patient's eye, comprising:surgically implanting in the eye a swell loadable polymeric ocularinsert with a micron scale tab that extends through the sclera as anexternal mass transport channel; and placing a therapeutic agent incontact with the ocular insert to thereby load the insert with theagent.
 31. The method of claim 30, wherein the placing the therapeuticagent comprises one of: dropping onto the eye eyedrops containing thetherapeutic agent; and applying to the eye an eye wash containing thetherapeutic agent.
 32. The method of claim 30, wherein the placing thetherapeutic agent comprises placing an appliance impregnated with theagent adjacent to and in removable contact with the scela and the tab;and transferring from the appliance to the interior of the eye throughthe tab the therapeutic agent impregnated in the appliance.
 33. Themethod of claim 32, wherein the appliance comprises a lens body formedof a block copolymer that is phase nanophase-separated to form aperiodic nanostructure of therapeutic agent-miscible domainsinterspersed among a hydrogel matrix, wherein the therapeutic agent isimpregnated in the agent-miscible domains.
 34. The method of claim 32,further comprising: removing the appliance from contact with the eye;placing a second time an appliance adjacent to and in removable contactwith the sclera and the tab; and transferring from the second placedappliance to the interior of the eye through the tab a therapeutic agentimpregnated in the appliance.
 35. The method of claim 32, furthercomprising: removing the appliance from contact with the eye;re-impregnating the appliance with a therapeutic agent; and replacingthe re-impregnated appliance adjacent to and in removable contact withthe sclera and the tab.
 36. A drug-delivering contact lens system forplacement in an eye, comprising: a removable lens body comprisingtherapeutic receiving domains; a therapeutic agent impregnated into thetherapeutic agent receiving domains; a transport device implantable inthe eye and capable of absorbing the therapeutic agent in a presence ofthe removable lens body external to the eye, and capable of deliveringthe therapeutic agent to an interior portion of the eye.
 37. The systemof claim 36, wherein the removable lens body is removed aftersubstantial absorbing of the therapeutic agent by the transport device.38. The system of claim 36, wherein the receiving domains are too smallto scatter visible light.
 39. The system of claim 36, wherein thereceiving domains comprise a hydrogel matrix.
 40. The system of claim39, wherein the hydrogel matrix comprises HEMA or a silicone material.41. The system of claim 39, wherein the receiving domains are morehydrophobic than the hydrogel matrix.
 42. The system of claim 36,wherein the lens body is formed of one of PEA, a polymer made throughmetathesis polymerization, and a polymer made by controlled free radicalpolymerization.
 43. The system of claim 36, wherein the lens body isreloadable with a fresh aqueous solution containing the therapeuticagent.
 44. The system of claim 43, wherein the transport device iscorrespondingly reloaded with the fresh aqueous solution containing thetherapeutic agent.
 45. The system of claim 36, wherein the transportdevice is implantable through the sclera of the eye.
 46. The system ofclaim 36, wherein the removable lens body is configured to be placed onthe cornea of the eye.